Alzheimer's Disease (AD) represents a major chronic health problem in the US and abroad. MRI studies of AD demonstrated a decrease in the size of the hippocampus and other brain structures associated with learning and memory. Toxic proteins, like A and tau, accumulate in these brain regions, and MRS and PET imaging studies consistently showed metabolic deficits and oxidative stress in brains of patients with AD. Advances in treatment of AD have been made by delivering neuronal stem cells, viral vectors, or drugs that can increase brain derived neurotrophic factor (BDNF) levels in the brain. BDNF promotes neuronal plasticity and restores brain functions. However, BDNF cannot cross an intact blood brain barrier (BBB), and is unstable in the blood or when delivered orally. The goal of this effort is to produce non-toxic, BDNF-nanoparticles (NPs), and to test the hypothesis that these NPs bypass the BBB intranasally, deliver BDNF to the brain, improve learning and memory, and reverse metabolic abnormalities and oxidative stress in the 3xTg mouse model of AD. To accomplish these goals we will design a two-part nanoparticle (<50 nanometers). A nanocarrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting molecules into cells. The second component will be a BDNF protein drug. BDNF will be attached to polyethylene glycol (PEG) molecules coating the carrier. A series of studies will ascertain the NP stability, specificity, brain distribution and functionality in vivo. The 3xTG mice will be treated with NPs or placebo early in the course of the disease for 10 weeks. Cognitive testing and Magnetic Resonance Spectroscopy (MRS: 1H and 31P) will be performed before and after treatment. We plan to demonstrate the feasibility of this novel nanotechnology to prevent memory problems, and treat early metabolic, oxidative and synaptic dysfunctions associated with AD. If this research project is successful it will provide new noninvasive nanotechnology tools for early treatment of AD. The new nanotechnology may be able to enhance neuronal metabolism and plasticity, and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular nanoparticle may also provide a major new tool for research of molecular abnormalities in AD. This novel nanotechnology may serve as the basis for a next generation drug-delivery system that can specifically target relevant brain systems, and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.